Findings

This was the fourth AD-associated mutation discovered involving codon 717 in APP. It was first reported in an American family in which the proband was diagnosed with Alzheimer's disease at age 38. Her presentation was typical for her family, with short-term memory problems appearing in the mid- to late 30s and gradual deterioration over approximately 10 years. The mean age of onset in this family was 38 years (range: 35 to 39 years) based on data from four affected family members (Murrell et al., 2000).

Another kindred, known as "Family 171," was also found to carry this mutation. This Caucasian family of English ancestry had a later age of onset. The mean age of onset for the seven affected family members was 50 years (range: 48 to 57 years). The mean age at death was 61 years (range: 57 to 68 years). In addition to the progressive memory impairment typical of AD, some members of this family also experienced seizures and hallucinations (Godbolt et al., 2006).

Two additional unrelated patients of German origin were also found to carry this mutation. One patient, identified as P. 43, had dementia onset at age 50 and a family history of dementia. The other, identified as P. 83, had dementia onset at age 43 and a family history of dementia (Finckh et al., 2005).

This mutation was detected in a Japanese family affected by early onset Alzheimer’s disease. The reported pedigree shows nine affected family members over three generations. The average age at onset in this family was 47.1 ± 3.1 years (range: 42 to 52 years). Typical of his family, the proband developed short-term memory loss and concentration deficits at age 45. Other symptoms in this family included psychiatric symptoms (e.g., depression, irritability, emotional lability), seizures, myoclonus, gait disturbance, and pyramidal signs. The mutation was not detected in 50 unrelated controls. MRI showed relatively minor atrophic changes in the bilateral hippocampus and cerebral cortices (Abe et al., 2012).

Additional reports of mutation carriers include another kindred (Ghetti et al., 2008) and an individual Caucasian patient affected by early onset AD (onset at age 59) whose diagnosis was confirmed by autopsy (Sassi et al., 2014).

Neuropathology

MRIs of affected members of the Japanese family showed relatively minor atrophic changes in the bilateral hippocampus and cerebral cortices (Abe et al., 2012).

Biological Effect

In primary mouse neurons this mutation increases the Aβ42/Aβ40 ratio by increasing levels of Aβ42 and decreasing levels of Aβ40 (De Jonghe et al., 2001). It has been predicted to be "possibly damaging" in silico (Sassi et al., 2014).